Delivery of therapeutic siRNA to the lung endothelium via novel Lipoplex formulation DACC.

Posttranscriptional gene silencing by RNA interference can be therapeutically exploited to inhibit pathophysiological gene expression. However, in contrast to the established effectiveness of RNAi in vitro, safe and effective delivery of siRNAs to specific organs and cell types in vivo remains the major hurdle. Here, we report the development and in vivo characterization of a novel siRNA delivery system (DACC lipoplex) suitable for modulating target gene expression specifically in the lung vasculature. Systemic administration of DACC in mice delivered siRNA cargo functionally to the lung pulmonary endothelium. A single dose of DACC lipoplexes administered by bolus injection or by infusion was sufficient to specifically silence genes expressed in pulmonary endothelial cells such as CD31, Tie-2, VE-cadherin, or BMP-R2. When tested in a mouse model for lung cancer, repeated treatment with DACC/siRNA(CD31) reduced formation of lung metastases and increased life span in a mouse model of experimental lung metastasis.

Intraoperative neuromonitoring in non-idiopathic pediatric scoliosis operated with minimally fusionless procedure: A series of 290 patients.

BACKGROUND: One of the worst complications of surgery for spinal deformity is postoperative neurological deficit. Multimodal intraoperative neuromonitoring (IONM) can be used to detect impending neurological injuries. This study aimed to analyze IONM in non-idiopathic scoliosis using a minimally invasive fusionless surgical technique. METHODS: This retrospective, single-center study was performed from 2014 to 2018. Patients with non-idiopathic scoliosis who underwent a minimally invasive fusionless procedure and had at least 2 years of follow-up were included. IONM was performed using a neurophysiological monitoring work station with somatosensory evoked potentials (SSEP) and neurogenic mixed evoked potentials (NMEP). RESULTS: A total of 290 patients were enrolled. The mean age at surgery was 12.9±3 years. The main etiology was central nervous system (CNS) disorders (n=139, 48%). Overall, 35 alerts (11%) in the SSEP and 10 (7%) in the NMEP occurred. There were two neurological deficits with total recovery after 6 months. There were no false negatives in either SSEP or NMEP, although there was one false positive in SSEP and two false positives for NMEP in the group without signal recovery. There was no significant relationship between the incidence of SSEP or NMEP loss and age, body mass index (BMI), number of rods used, upper instrumented vertebrae (p=0.36), lower instrumented vertebrae, or type of surgery. A preoperative greater Cobb angle was associated with a significantly higher risk of NMEP loss (p=0.02). In CNS patients, a higher BMI was associated with a statistically significant risk of NMEP loss (p=0.004). The use of a traction table was associated with a higher risk of signal loss (p=0.0005). CONCLUSION: A preoperative higher Cobb angle and degree of correction were associated with a significant risk of NMEP loss. In CNS scoliosis, a higher BMI was associated with a significant risk of NMEP loss. The use of a traction table was associated with a higher risk of signal loss.

Electro-clinical features in epileptic children with chromosome 15q duplication syndrome.

OBJECTIVE: We aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15). METHODS: Clinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis. RESULTS: Seventy video-EEGs were analyzed (1-16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age. CONCLUSION: WS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay. SIGNIFICANCE: This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.

Melatonin: experience in its use for recording sleep EEG in children and review of the literature.

BACKGROUND: Sleep is known to improve the yield of EEG recording in children but is often difficult to obtain. In order to evaluate the efficacy and to test the practicability of oral melatonin in obtaining sleep for EEG recording, we studied its use in 70 children. RESULTS: Sleep was obtained in 56 children (80%) with a mean sleep latency onset of 25 ± 7.9 min (15-45) after melatonin administration, and a mean sleep duration of 17.1 ± 8.6 min (5-55). 28 children (50%) woke up spontaneously after 13.2 ± 7.9 min (5-40). Among 18 children with severe behaviour problems that made interpretable EEG recording in the awake state impossible, sleep was obtained in 13 (72%) children. The rare symptoms reported (4%) were not reliably related to the use of melatonin. CONCLUSION: The study shows a very good efficacy in sleep induction for EEG recording, even in children with severe behaviour problems. Sleep duration was, however, short with a high proportion of spontaneous arousals but in all patients it was sufficient for an initial diagnosis or control of the evolution of epilepsy.

Child EEG (and maturation).

EEG changes during the perinatal period, infancy, childhood, and adolescence are concomitant with brain growth, myelination, expanding connectivity, and overall maturation, which are particularly fast during the first year of life. EEG aspects of early brain development are accessible in preterm during the third trimester of gestational age, and they evolve to full-term, infancy, and childhood EEG patterns. Each of these age periods shares specific EEG features that reach gross adult outlines in the first year. Interpreting EEG needs therefore a deep knowledge of pathological and normal EEG patterns with their variants belonging to each age range. Recording EEG during these periods also requires adapting the recording techniques to the specific age in order to obtain interpretable records. This chapter describes normal EEG features and variants, characteristic patterns of development, and some patterns that are unusual for age, from the neonatal period to adolescence.

[Epilepsy and focal lesions in children. Surgical management]. / Epilepsie et lésions focales chez l'enfant. Traitement chirurgical.

Epilepsy surgery has gained a large role in the treatment of intractable seizures in the last few decades because of the development of operative techniques and better identification of the cerebral anomalies using electrophysiological recordings and neuroimaging. A series of 419 children, aged from five months to 15 years, with epilepsy (medically refractory in 85.5% of them) associated with focal cortical lesions, who underwent surgery between 1986 and 2006 was analyzed to identify the factors that correlated with outcome. Mean follow-up was 5.2 years. According to Engel's classification; 75.8% of the children were seizure-free. When the lesion was well defined, correlations between clinical data, radiological features and electrophysiological features, suggesting a zone of seizure onset around (or even in) the lesion, was the best guarantee of achieving good seizure control by lesionectomy. Nevertheless, seizure outcome was also determined by other factors: the duration of the epilepsy and the surgery. Persistence of seizures was found to be significantly associated with the preoperative duration of epilepsy, the completeness of the lesional resection and de novo brain damage induced by the surgical procedure itself. Early surgery must be considered in children because of the benefits of seizure control on the developing brain and the risk of secondary epileptogenesis.

[Epilepsy in chromosome aberrations]. / L'épilepsie dans les aberrations chromosomiques.

Epilepsy is among the most frequent finding in many chromosome aberrations. While most chromosome aberrations can be associated with different seizure types, there are few aberrations which feature specific seizures and EEG patterns. Among the 400 different chromosomal imbalances described with seizures and EEG abnormalities, eight have a high association with epilepsy. These comprise: the monosomy 1p36, Wolf-Hirschhorn syndrome (4p-), Angelman syndrome, Miller-Dieker del 17p13.3, the inversion duplication 15 syndrome, ring 20 and ring 14 syndromes, Down's syndrome. These chromosomal regions where aberrations have an evident association with epilepsy may be useful targets for gene hunters. On the other hand, a better characterisation of epileptic syndrome in these disorders may lead to a better and specific treatment.

EEG in children, in the laboratory or at the patient's bedside.

In pediatrics, EEG recordings are performed on patients from the neonatal period up to young adults. This means adapting techniques to many different conditions, concerning not only the patient's age, the need for asepsis and the patient's behavior, but also the environment (e.g. in the laboratory, at the patient's bedside, or in the neonatal intensive care unit [NICU]). Technical requirements depend on age, indication and the type of examination; in infancy, there should be a minimum of 12 EEG electrodes, ECG and respiration recording. In epileptology, surface EMG is also necessary to characterize the type of seizures and refine the diagnosis of epilepsy syndrome, on which physicians will base their treatment choice. The role of the EEG technician is essential because the quality of the recording, its analysis and conclusion will depend on the quality of the technical set-up and the interaction with the child. Sleep is a systematic part of the study up to the age of 5 years for several reasons: sleep EEG yields information on brain maturation; the EEG tracing during wakefulness can contain too many artefacts; and some grapho-elements, key to the diagnosis, only appear during sleep. The time of the examination must be chosen according to the child's usual nap times, possibly after sleep deprivation. Grapho-elements and spatio-temporal organization of the EEG vary with age, and normal variants and unusual aspects are quite wide for any given age; this is why a physician experienced in pediatric EEG should perform the interpretation. This chapter concerns EEG performed in infants, children and adolescents, its technical aspects according to age and indications (general pediatrics, emergency, epilepsy).

[French guidelines on electroencephalogram]. / Recommandations françaises sur l'électroencéphalogramme.

Electroencephalography allows the functional analysis of electrical brain cortical activity and is the gold standard for analyzing electrophysiological processes involved in epilepsy but also in several other dysfunctions of the central nervous system. Morphological imaging yields complementary data, yet it cannot replace the essential functional analysis tool that is EEG. Furthermore, EEG has the great advantage of being non-invasive, easy to perform and allows control tests when follow-up is necessary, even at the patient's bedside. Faced with the advances in knowledge, techniques and indications, the Société de Neurophysiologie Clinique de Langue Française (SNCLF) and the Ligue Française Contre l'Épilepsie (LFCE) found it necessary to provide an update on EEG recommendations. This article will review the methodology applied to this work, refine the various topics detailed in the following chapters. It will go over the summary of recommendations for each of these chapters and underline proposals for writing an EEG report. Some questions could not be answered by the review of the literature; in those cases, an expert advice was given by the working and reading groups in addition to the guidelines.

Normal EEG in childhood: from neonates to adolescents.

The important EEG changes that occur throughout childhood are a major challenge for the neurophysiologist. These reflect brain maturation, which is especially fast during the first year of life. This article describes normal EEG features and variants, characteristic patterns of development, as well as some patterns that are unusual for age, from the neonatal period to adolescence. We also describe how to adapt techniques and prepare patients in order to get interpretable records of appropriate duration, in neonates, infants, and young children.